Wnt/beta-catenin signaling controls development of the blood-brain barrier.
The blood-brain barrier (BBB) is confined to the endothelium of brain capillaries and is indispensable for fluid homeostasis and neuronal function. In this study, we show that endothelial Wnt/beta-catenin (beta-cat) signaling regulates induction and maintenance of BBB characteristics during embryonic and postnatal development. Endothelial specific stabilization of beta-cat in vivo enhances barrier maturation, whereas inactivation of beta-cat causes significant down-regulation of claudin3 (Cldn3), up-regulation of plamalemma vesicle-associated protein, and BBB breakdown. Stabilization of beta-cat in primary brain endothelial cells (ECs) in vitro by N-terminal truncation or Wnt3a treatment increases Cldn3 expression, BBB-type tight junction formation, and a BBB characteristic gene signature. Loss of beta-cat or inhibition of its signaling abrogates this effect. Furthermore, stabilization of beta-cat also increased Cldn3 and barrier properties in nonbrain-derived ECs. These findings may open new therapeutic avenues to modulate endothelial barrier function and to limit the devastating effects of BBB breakdown.
Liebner
Stefan
S
Institute of Neurology (Edinger Institute), Johann Wolfgang Goethe University, 60325 Frankfurt, Germany. elisabetta.dejana@ifom-ieo-campus.it
Corada
Monica
M
Bangsow
Thorsten
T
Babbage
Jane
J
Taddei
Andrea
A
Czupalla
Cathrin J
CJ
Reis
Marco
M
Felici
Angelina
A
Wolburg
Hartwig
H
Fruttiger
Marcus
M
Taketo
Makoto M
MM
von Melchner
Harald
H
Plate
Karl Heinz
KH
Gerhardt
Holger
H
Dejana
Elisabetta
E
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002490:Central Nervous System / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000502:physiology*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D051153:Wnt Proteins; D051176:beta Catenin; D001616:beta-Galactosidase